Osteopontin (OPN) is a multifunctional, secreted phosphoprotein with beneficial anticalcific effects[unreadable] on pathological calcification. Recent data suggest that OPN may also play a critical role in[unreadable] development of various chronic inflammatory diseases, including atherosclerosis. Furthermore,[unreadable] growing evidence indicates that multiple, proteolytically processed forms of OPN are generated[unreadable] under inflammatory conditions. However, virtually nothing is known about the specific form(s) and[unreadable] function(s) of OPN important in these settings. We propose that a common feature of chronic[unreadable] inflammatory conditions is a requirement for OPN function in macrophages. Specifically, we[unreadable] hypothesize that 1) OPN mediates macrophage recruitment, activation, and survival in[unreadable] atherosclerotic plaques, 2) thrombin, as well as matrix metalloproteases secreted by inflammatory[unreadable] cells modify OPN activity, and 3) that specific OPN proteolytic fragments are required for plaque[unreadable] progression in vivo. Three Specific Aims are proposed to address these hypotheses. In Specific[unreadable] Aim 1, the role of macrophage- and lymphocyte-derived OPN in atherosclerotic lesion initiation and[unreadable] progression in chow-fed ApoE-/- mice will be determined using bone marrow transplant studies. In[unreadable] Specific Aim 2, the role of OPN and its receptors in the modulation of macrophage functions in vitro,[unreadable] including adhesion, migration, survival and activation, will be examined. Finally, in Specific Aim 3,[unreadable] the role of two integrin binding domains, RGD and SLAYGLR domains, of OPN as well as MMPderived[unreadable] OPN proteolytic fragments will be determined during atherosclerotic lesion development[unreadable] and progression in ApoE-/- mice using bone marrow over-expressing these OPN fragments on a[unreadable] macrophage specific promoter. Understanding differences in the mechanisms and[unreadable] structure/function relationships governing inflammatory properties of OPN could help create specific[unreadable] therapeutics targeting these distinct functions.